Disease relevance of HSDB 4300

• The toxicity of macrocyclic pyrrolizidine alkaloids in the livers of man and animals has been attributed to the formation of reactive pyrroles from dihydropyrrolizines [1].
• The results indicate that DHH is responsible for some, possibly most, of the carcinogenicity of the parent pyrrolizidine alkaloids and also stimulates the earlier and more rapid development of renal and vascular diseases normally associated with aging in rats [2].
• When dehydroheliotridine (DHH), a pyrrolizidine alkaloid metabolite with bifunctional alkylating and antimitotic activities, was administered to a hooded strain of rats by ip injection, the incidence of tumors, excluding interstitial cell tumors, was significantly greater than that in saline-injected controls [2].
• An infant with documented hepatic veno-occlusive disease due to ingestion of pyrrolizidine alkaloids is presented [3].
• We hypothesize that this change is analogous to the hypertrophy and mitotic inhibition that occurs in the liver of animals treated with hepatotoxic pyrrolizidine alkaloids [4].

Psychiatry related information on HSDB 4300

• Most progeny are sired exclusively by one male, the larger one, irrespective of parental age, male pyrrolizidine alkaloid content, mating order, between-mating interval, or duration of copulation [5].
• In order to develop drugs effective against Alzheimer's disease, we synthesized a series of aniline derivatives having a characteristic cyclic amine, 1-azabicyclo[3.3.0]octane ring, and evaluated their binding affinity for the central muscarinic cholinergic receptor [6].

High impact information on HSDB 4300

• Female Swiss mice susceptible to skin tumors received 6 sc injections and/or topical applications of dehydroretronecine, a metabolite of the pyrrolizidine alkaloid monocrotaline, and were observed for 15 months for tumor development [7].
• METHODS: In vitro and in vivo studies examined changes induced by monocrotaline, a pyrrolizidine alkaloid that induces sinusoidal obstruction syndrome in both humans and experimental animals [8].
• Homospermidine synthase, the first pathway-specific enzyme of pyrrolizidine alkaloid biosynthesis, evolved from deoxyhypusine synthase [9].
• Retrorsine is a member of the pyrrolizidine alkaloid family of compounds whose toxic effects on the liver include a long-lasting inhibition of the proliferative capacity of hepatocytes [10].
• trans-4-Hydroxy-2-hexenal (t-4HH), a reactive metabolite isolated from the pyrrolizidine alkaloid senecionine, and trans-4-hydroxy-2-nonenal (t-4HN), a product of lipid peroxidation, reacted nonenzymatically with deoxyguanosine at pH 7.4 at 37 degrees C in vitro with each compound yielding two pairs of diastereomeric adducts [11].

Chemical compound and disease context of HSDB 4300

• Toxicity and pharmacokinetics of a pyrrolizidine alkaloid, indicine N-oxide, in humans [12].
• Lasiocarpine (LC), a pyrrolizidine alkaloid, is able to induce a series of chronic and progressive lesions in rat liver, including a long-lasting block in the cell cycle, the appearance of enlarged hepatocytes (megalocytosis), fibrosis, cirrhosis and malignant neoplasma [13].
• Pulmonary heart disease induced by disenecioyl dehydroretronecine: a semisynthesis pyrrolizidine alkaloid pyrrole [14].
• Effects of taurine and guanidinoethane sulfonate on toxicity of the pyrrolizidine alkaloid monocrotaline [15].
• Clivorine, a naturally occurring pyrrolizidine alkaloid, causes liver toxicity via its metabolic activation to generate toxic metabolite (pyrrolic ester) [16].

Biological context of HSDB 4300

• Sequence comparison provides direct evidence for the evolutionary recruitment of an essential gene of primary metabolism (DHS) for the origin of the committing step (HSS) in the biosynthesis of pyrrolizidine alkaloids [9].
• Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline [17].
• Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV+ Fischer 344 rats were transplanted into the liver of DPPIV- mutant Fischer 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy [18].
• Liver regeneration after two-thirds surgical partial hepatectomy (PH) in rats treated with the pyrrolizidine alkaloid retrorsine is accomplished through the activation, expansion, and differentiation of a population of small hepatocyte-like progenitor cells (SHPCs) [19].
• In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect of their patterns of alkylation (at the 2-amino group of guanine) [20].

Anatomical context of HSDB 4300

• These studies suggest that the hepatocarcinogenicity of pyrrolizidine alkaloids can be better explained by their strong selection (promotion) influence on initiated hepatocytes, rather than by their very weak initiating activity [21].
• Monocrotaline pyrrole (MCTP), a metabolite of the pyrrolizidine alkaloid monocrotaline, is thought to initiate damage to pulmonary endothelial cells resulting in delayed but progressive pulmonary interstitial edema, vascular wall remodeling, and increasing pulmonary hypertension [22].
• They were given 2 doses of the pyrrolizidine alkaloid retrorsine (30 mg/kg, i.p.), 2 weeks apart, followed 2 weeks later by transplantation of 2 x 10(6) hepatocytes (via the portal vein), freshly isolated from a normal congeneic DPPIV+ donor [23].
• A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay [24].
• Na+/K(+)-adenosine triphosphatase activity of pulmonary arteries after intoxication with the pyrrolizidine alkaloid, monocrotaline [25].

Associations of HSDB 4300 with other chemical compounds

• Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine [21].
• Australine [(1R,2R,3R,7S,7aR)-3-(hydroxymethyl)-1,2,7-trihydroxypyrrolizid ine] is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis [Molyneux et al. (1988) J. Nat. Prod. (in press)] [26].
• Administration of monocrotaline, a pyrrolizidine alkaloid, to male Sprague-Dawley rats for up to three weeks increased dry lung weights by 64% and reduced the specific activity of lung angiotensin-converting enzyme activity by 64% [27].
• The gender differences in the in vitro microsomal metabolic activation of hepatotoxic clivorine, a representative naturally occurring hepatotoxic otonecine type pyrrolizidine alkaloid, in Sprague-Dawley rats and their relation to the gender differences in susceptibility to clivorine intoxication were reported in the present study [28].
• The association of radiolabeled monocrotaline pyrrole (DHM) with red blood cell (RBCs) ghosts, globins, and heme was examined to determine their role in the transport and stabilization of this hepatic produced putative toxic metabolite of the pyrrolizidine alkaloid monocrotaline (MCT) [29].

Gene context of HSDB 4300

• These observations suggested the potential involvement of the male-specific cytochrome P-450 UT-A and the P-450 PCN-E in the metabolism of this pyrrolizidine alkaloid [30].
• Under oxidative conditions, reduction of the N-oxide to pyrrolizidine alkaloid is inhibited and while under hypoxic conditions, DHP formation is dramatically decreased [31].
• These studies document the effects of pyrrolizidine alkaloid clivorine on the MAPK cascade and on the growth of human normal liver L-02 cells for the first time, which may be a possible reason for the toxic effects observed in those plants containing pyrrolizidine alkaloids [32].
• Moreover, another pyrrolizidine alkaloid monocrotaline had no effect on phosphorylation of p38 MAP Kinase in L-02 cells [32].
• A series of naphthalene derivatives substituted with the 1-azabicyclo[3.3.0]octane ring were also synthesized and muscarinic M1 and M2 receptor binding affinity determined [33].

Analytical, diagnostic and therapeutic context of HSDB 4300

• Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two-thirds partial hepatectomy (PH) [34].
• Treatment of rats with retrorsine, a pyrrolizidine alkaloid, blocks endogenous hepatocytes from proliferating, so that after exposure to this agent coupled with PH and hepatocyte transplantation, transplanted hepatocytes selectively repopulate the liver [35].
• We have investigated the role of angiotensin converting enzyme (ACE) in the development of pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular disease in rats given a single subcutaneous injection of the pyrrolizidine alkaloid monocrotaline [36].
• Dynamic pH junction-sweeping capillary electrophoresis for online preconcentration of toxic pyrrolizidine alkaloids in Chinese herbal medicine [37].
• Dehydroretronecine (DHR), a major metabolite of the pyrrolizidine alkaloids, has been shown to bind and crosslink pBR322 plasmid DNA and M13 viral DNA, as monitored by electron microscopy and agarose gel electrophoresis [38].

References